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Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Duke University
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Anne Beaven, MD, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00978432
First received: September 15, 2009
Last updated: May 21, 2014
Last verified: May 2014
  Purpose

The purpose of this study is evaluate the response, safety and tolerability in subjects receiving the investigational drugs, RAD001 and LBH589.


Condition Intervention Phase
Diffuse Large B-cell Lymphoma
Drug: RAD001
Drug: LBH589
Drug: RAD001 and LBH589 as a doublet
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Overall response rate [ Time Frame: From the start of combination therapy until a maximum of 2 years after completion of therapy ] [ Designated as safety issue: No ]
    Overall Response Rate is the number of participants with a partial and complete response assessed by the Updated Cheson criteria for lymphoma. A complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy and normalization of those biochemical abnormalities. If a subject has residual lesions on CT scan and the disease was FDG avid pre-treatment, then that subject will be considered to be in a complete response. Partial response is a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease

  • Assessment of association between observed response to RAD001 and LBH589 and the response predicted by molecular signatures developed in our pre-clinical model [ Time Frame: From the start of combination therapy until a maximum of 2 years after completion of therapy ] [ Designated as safety issue: No ]
    We will estimate the association of the molecular signature-predicted response to the doublet (CR+PR) with the observed response. All evaluable patients will be used in estimating response. The chi-square test with one-sided alpha of 0.10 will be used to test for the association between predicted and observed responses. Contingency tables will be used to present these associations.


Secondary Outcome Measures:
  • Summary of Adverse Events (AEs) [ Time Frame: From the time of first dose of study drug until 4 weeks after participant has stopped study drug ] [ Designated as safety issue: Yes ]
    Counts of participants who had adverse events or treatment-emergent adverse events (TEAE, defined as newly occurring or worsening after first dose). National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) is used to assess severity. Relatedness to study drug is assessed by the investigator.

  • Distribution of change across time of mTOR and HDAC-I inhibition from baseline until after the 1st 2 cycles of study drug in patients who received LBH and RAD. [ Time Frame: after 2 cycles of study therapy ] [ Designated as safety issue: No ]
    Serum markers will be measured on the first day of cycle 1 and on the first day of cycle 3. The distribution of change across time in a marker will be summarized.

  • Evaluate the association of observed response to the doublet with the response predicted by molecular signatures for activated B cell like (ABC) DLBCL and for Germinal Center B cell like (GCB) DLBCL. [ Time Frame: up to 13 cycles of therapy ] [ Designated as safety issue: No ]
    Response rates seen in subjects with activated B cell like DLBCL and for Germinal center B cell like DLBCL will be reported and assessed to see if GCB is associated with improved outcomes compared to ABC in subjects with relapsed disease who have received RAD + LBH. We will estimate the association of the ABC and GCB with the observed response. All evaluable patients will be used in estimating response. The chi-square test with one-sided alpha of 0.10 will be used to test for the association between predicted and observed responses.


Estimated Enrollment: 75
Study Start Date: February 2012
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: RAD001
    10 mg/day for Part 1 of the trial
    Other Name: Everolimus
    Drug: LBH589
    40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial
    Other Name: panobinostat
    Drug: RAD001 and LBH589 as a doublet
    RAD001 10 mg on Monday/Wednesday/Friday during Part 2 LBH589 20 mg during Part 2
Detailed Description:

This will be a prospective, non-randomized, un-blinded phase 2 efficacy trial using an mTOR inhibitor and a histone deacetylase (HDAC) inhibitor for epigenetic targeted therapies.

Subjects will receive RAD001 and LBH589 given in four to thirteen, 28-day cycles. Subjects with progressive disease will stop after 4 cycles. Subjects with stable disease or better after 4 cycles may receive up to 13 cycles. LBH will start at 20mg po on days M/W/F and RAD001 will start at 10mg po daily.

Treatment will be administered on an outpatient basis. Patients will be followed for up to 2 years after completion of therapy or until progression of disease or death.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically or cytologically confirmed diffuse large B cell non-Hodgkin lymphoma (DLBCL) that is de novo or transformed. Based on the revised 2008 WHO criteria subjects with DLBCL-like lymphomas will also be allowed including the list below, although this list is not all-inclusive.

    • DLBCL
    • EBV+ DLBCL in elderly,
    • DLBCL associated with chronic inflammation,
    • Primary cutaneous DLBCL, leg type,
    • B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma,
    • B cell lymphoma unclassifiable with features intermediate between large B cell lymphoma and classical Hodgkin lymphoma,
    • ALK+ large B cell lymphoma,
    • T cell histiocyte rich large B cell lymphoma
    • Primary mediastinal B cell lymphoma
    • Follicular grade 3 B cell lymphoma
  2. Refractory or relapsed disease to at least one prior treatment regimen, which should include autologous stem cell transplant unless the patient refused or was ineligible for transplant for any reason.
  3. Age > 18 years old
  4. ECOG performance status of <2.
  5. Measurable or evaluable disease based on physical exam and/or radiographs or bone marrow involvement
  6. Have a frozen tumor or paraffin-embedded sample available for for gene expression using a previously collected sample unless a new biopsy is needed for clinical management of the patient.
  7. At least 3-4 core biopsy specimens using at least a 18 gauge needle. An equivalent amount of biopsy material from previously performed procedures, as long as it was fresh frozen, can be used in lieu of freshly obtained tissue. FNA is not acceptable for this initial specimen. Leukapheresis sample may be obtained instead of core biopsy for patients with leukocytosis.
  8. Laboratory Values as per protocol.

Exclusion Criteria:

  1. Laboratory Values

    • Grade 3 hyperlipidemia (Serum cholesterol >400mg/dl or serum triglycerides >5 x ULN) despite optimal supportive medical therapy
    • Serum Glucose > 250mg/dl on at least two checks on two separate days despite optimal medical management
    • Patients with diabetes may be enrolled on the trial as long as their sugars are adequately controlled
  2. No limit to the number of prior chemotherapy regimens, however:

    • No prior exposure to RAD001 or LBH589 or to any drugs that mainly target mTOR (everolimus, sirolimus, temsirolimus etc) or HDAC (vorinostat)

      • Valproic acid is a mild HDAC inhibitor so patients may not receive valproic acid at any time during the study or for the 5 days preceding starting the first study drug.
    • No chemotherapy, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received BCNU or mitomycin C). Subjects must have recovered from all therapy-related non-hematological toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity.
    • No time limit with regards to radiation prior to registration.
    • No radioimmunotherapy within 2 months prior to registration. Subjects must have recovered from all therapy-related toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity.
    • No prior allogeneic stem cell transplantation unless allogeneic engraftment is <2%.
    • Subjects receiving chronic, systemic treatment with corticosteroids equivalent to >20mg of prednisone per day.

      • Subjects receiving replacement for adrenal insufficiency will be allowed on the study.
      • Topical or inhaled corticosteroids are allowed.
  3. Subjects with a history of another primary malignancy < 3 years ago, with the exception of inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a PSA that has not increased for at least 3 months, carcinoma in situ of the cervix.
  4. Major surgery < 4 weeks prior to registration. Minor surgery < 2 weeks prior to registration. Subjects must have recovered from all surgery related toxicities to < grade 1 or to baseline if subject started with > grade 1 toxicity.
  5. Subjects who have received investigational drugs < 4 weeks prior to registration.
  6. Impaired Cardiac Function as per protocol.
  7. Female patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control will be excluded from this trial.
  8. DLCO < 40% if tested (per protocol).
  9. Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry.
  10. Immunization with live attenuated vaccines within 1 week of study entry
  11. Impairment of GI function or GI disease that may alter absorption of RAD001 or LBH589
  12. Concurrent severe &/or uncontrolled medical conditions
  13. Using meds that have a relative risk of prolonging QT interval or inducing torsade de pointes or otherwise interacting with LBH and RAD001 may be used per the protocol.
  14. Active bleeding tendency
  15. Known positivity for HIV.
  16. Known positivity for HCV. Baseline testing per protocol.

16. History of non-compliance to medical regimens.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00978432

Contacts
Contact: Peggy Alton, RN, BSN 919-681-4769 peggy.alton@duke.edu
Contact: Patricia Davis, RN 919--668-1026 davis043@mc.duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Principal Investigator: Anne W. Beaven, MD         
Sponsors and Collaborators
Anne Beaven, MD
Novartis
Investigators
Principal Investigator: Anne W. Beaven, MD Duke University
  More Information

Additional Information:
No publications provided

Responsible Party: Anne Beaven, MD, Assistant Professor of Medicine, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00978432     History of Changes
Other Study ID Numbers: Pro00012947
Study First Received: September 15, 2009
Last Updated: May 21, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
NHL
DLBCL
recurrent
refractory
de novo

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Everolimus
Panobinostat
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 19, 2014